N-acyl and N-aroyl aralkyl amides as serotonergic agents

ABSTRACT

A compound of the formula                    
     wherein m, R 1 , R 2 , R 3 , R 4 , R 5  and X are as defined above, useful in treating or preventing migraine, depression and other disorders for which a 5-HT 1  agonist or antagonist is indicated.

The application is a division of U.S. Ser. No. 09/291,454, filed Apr.14, 1999, which application claims the benefit of U.S. provisionalpatent application No. 60/081,970, filed Apr. 16, 1998.

BACKGROUND OF THE INVENTION

The present invention relates to novel N-acyl and N-aroyl aralkylamides, to intermediates for their preparation, to pharmaceuticalcompositions containing them and to their medicinal use. The compoundsof the present invention include selective agonists and antagonists ofserotonin 1 (5-HT₁) receptors, specifically, of one or both of the5-HT_(1A) and 5-HT_(1D) receptors. They are useful in treating orpreventing migraine, depression and other disorders for which a 5-HT₁agonist or antagonist is indicated.

European Patent Publication 434,561, published on Jun. 26, 1991, refersto 7-alkyl, alkoxy, and hydroxysubstituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compoundsare referred to as 5-HT₁ agonists and antagonists useful for thetreatment of migraine, depression, anxiety, schizophrenia, stress andpain.

European Patent Publication 343,050, published on Nov. 23, 1989, refersto 7-unsubstituted, halogenated, and methoxysubstituted-1-(4-substituted-1-piperazinyl)-naphthalenes as useful5-HT_(1A) ligand therapeutics.

PCT publication WO 94/21619, published Sep. 29, 1994, refers tonaphthalene derivatives as 5-HT₁ agonists and antagonists.

PCT publication WO 96/00720, published Jan. 11, 1996, refers to naphthylethers as useful 5-HT₁ agonists and antagonists.

European Patent Publication 701,819, published Mar. 20, 1996, refers tothe use of 5-HT₁ agonists and antagonists in combination with a 5-HTre-uptake inhibitor.

Glennon et al., refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as auseful 5-HT₁ ligand in their article “5-HT_(1D) Serotonin Receptors”,Clinical Drug Res. Dev., 22, 25-36 (1991).

Glennon's article “Serotonin Receptors: Clinical Implications”,Neuroscience and Behavioral Reviews, 14, 35-47 (1990), refers to thepharmacological effects associated with serotonin receptors includingappetite suppression, thermoregulation, cardiovascular/hypotensiveeffects, sleep, psychosis, anxiety, depression, nausea, emesis,Alzheimer's disease, Parkinson's disease and Huntington's disease.

World Patent Application WO 95/31988, published Nov. 30, 1995, refers tothe use of a 5-HT_(1D) antagonist in combination with a 5-HT_(1A)antagonist to treat CNS disorders such as depression, generalizedanxiety, panic disorder, agoraphobia, social phobias,obsessive-compulsive disorder, post-traumatic stress disorder, memorydisorders, anorexia nervosa and bulimia nervosa, Parkinson's disease,tardive dyskinesias, endocrine disorders such as hyperprolactinaemia,vasospasm (particularly in the cerebral vasculature) and hypertension,disorders of the gastrointestinal tract where changes in motility andsecretion are involved, as well as sexual dysfunction.

G. Maura et al., J. Neurochem, 66 (1), 203-209 (1996), have stated thatadministration of agonists selective for 5-HT_(1A) receptors or for both5-HT_(1A) and 5-HT_(1D) receptors might represent a great improvement inthe treatment of human cerebellar ataxias, a multifaceted syndrome forwhich no established therapy is available.

SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula

or the pharmaceutically acceptable salt thereof, wherein

R¹ is a group of the formua G¹, G², G³, G⁴, G⁵ or G⁶ depicted below:

 wherein the broken line indicates an optional double bond;

a is zero to eight;

m is 0, 1, 2, 3 or 4;

p is 1, 2 or 3;

D is oxygen, sulfur, SO, SO₂, or NR⁷;

E is oxygen, sulfur, SO or SO₂;

X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C₁-C₆)alkyl,hydroxy, trifluoromethyl, (C₁-C₆)alkoxy, —S(O)_(t)(C₁-C₆)alkyl wherein tis 0, 1 or 2, —CO₂R¹⁰ or —CONR¹¹R¹²;

R² is —(CH₂)_(t)B, wherein t is 0, 1, 2 or 3, and B is hydrogen, phenyl,napthyl or a 5 or 6 membered heteroaryl group containing from one tofour heteroatoms in the ring, and wherein each of the foregoing phenyl,naphthyl and heteroaryl groups may optionally be substituted with one ormore substituents independently selected from chloro, fluoro, bromo,iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy-(C₁C₆)alkyl-,trifluoromethyl, trifluoromethoxy, cyano, hydroxy, —COOH and—SO_(n)(C₁-C₆)alkyl wherein n is 0, 1 or 2;

R³ and R⁴ are each independently hydrogen, (C₁-C₄)alkyl or —(CH₂)_(q)—Jwherein q is 0, 1, 2 or 3, and J is phenyl or naphthyl, wherein saidphenyl or naphthyl may be optionally substituted with one to threesubstituents independently selected from the group consisting of chloro,fluoro, bromo, iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyanoand —S(O)_(k)(C₁-C₆)alkyl wherein k is 0, 1 or 2;

R⁵ is hydrogen or (C₁-C₃)alkyl;

R⁶ is selected from the group consisting of hydrogen, (C₁-C₆)alkyloptionally substituted with (C₁-C₆)alkoxy or one to three fluorineatoms, or [(C₁-C₄)alkyl]aryl wherein the aryl moiety is phenyl,naphthyl, or heteroaryl-(CH₂)_(q)—, wherein the heteroaryl moiety isselected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl,benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one,two, three or four, and wherein said aryl and heteroaryl moieties mayoptionally be substituted with one or more substituents independentlyselected from the group consisting of chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyano and—SO_(g)(C₁-C₆)alkyl, wherein g is zero, one or two;

R⁷ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,[(C₁-C₄)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, orheteroaryl-(CH₂)_(r)—, wherein the heteroaryl moiety is selected fromthe group consisting of pyridyl, pyrimidyl, benzoxazolyl,benzothiazolyl, benzisoxazolyl and benzisothiazolyl and r is zero, one,two, three or four, and wherein said aryl and heteroaryl moieties mayoptionally be substituted with one or more substituents independentlyselected from the group consisting of chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, —C(═O)—(C₁-C₆)alkyl, cyanoand —SO_(j)(C₁-C₆)alkyl, wherein j is zero, one or two;

or R⁶ and R⁷ taken together form a 2 to 4 carbon chain;

R⁸ is hydrogen or (C₁-C₃)alkyl;

R⁹ is hydrogen or (C₁-C₆)alkyl;

or R⁶ and R⁹, together with the nitrogen atom to which they areattached, form a 5 to 7 membered heteroalkyl ring that may contain fromzero to four heteroatoms selected from nitrogen, sulfur and oxygen;

each of R¹⁰, R¹¹ and R¹² is selected, independently, from the radicalsset forth in the definition of R³; or R¹¹ and R¹², together with thenitrogen to which they are attached, form a 5 to 7 membered heteroalkylring that may contain from zero to four heteroatoms selected fromnitrogen, sulfur and oxygen; and

each R¹³ is, independently, (C₁-C₄)alkyl or a (C₁-C₄)methylene bridgefrom one of the ring carbons of the piperazine or piperidine ring of G¹or G², respectively, to the same or another ring carbon or a ringnitrogen of the piperazine or piperidine ring of G¹ or G², respectively,having an available bonding site, or to a ring carbon of R⁶ having anavailable bonding site;

with the proviso that when B is hydrogen, t is not zero; and

with the proviso that when the broken line in formula G² is a doublebond, R⁸ is absent.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula I. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,lactate, citrate, acid citrate, tartrate, bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of formula 1. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula I that are acidic innature are those that form non-to,xic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (eg, potassium and sodium) and alkaline earth metal cations(eg., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine-(meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

The compounds of this invention include all stereoisomers (e.g., cis andtrans isomers) and all optical isomers of compounds of the formula I(e.g., R and S enantiomers), as well as racemic, diastereomeric andother mixtures of such isomers.

The compounds of this invention may contain olefin-like double bonds.When such bonds are present, the compounds of the invention exist as cisand trans configurations and as mixtures thereof.

Unless otherwise indicated, the alkyl and alkenyl groups referred toherein, as well as the alkyl moieties of other groups referred to herein(e.g., alkoxy), may be linear or branched, and they may also be cyclic(e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linearor branched and contain cyclic moieties. Unless otherwise indicated,halogen includes fluorine, chlorine, bromine, and iodine.

The term “a 5 or 6 membered heteroaryl group containing from one to fourheteroatoms in the ring”, as used herein, unless otherwise indicated,includes but is not limited to furyl, thienyl, thiazolyl, pyrazolyl,isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl,imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,1,3,5-triazinyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl,benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl,benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indazolyl,isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl orbenzoxazinyl.

The term “a 5 to 7 membered heteroalkyl ring that may contain from oneto four heteroatoms selected from nitrogen, sulfur and oxygen”, as usedherein, unless otherwise indicated, includes but is not limited topyrrolidine, isoxazolidine, 1,3-oxazolidin-3-yl, isothiazolidine,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1 -yl,piperidine, thiomorpholine, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazine, morpholine,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, piperazine.

Preferred compounds of the formula I include those wherein R¹ is

R⁶ is (C₁-C₆)alkyl and R³ is hydrogen.

Other preferred compounds of formula I include those wherein R² isphenyl or benzyl optionally substituted by chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl or trifluoromethyl.

Other preferred compounds of formula I include those wherein R⁴ ishydrogen or (C₁-C₆)alkyl.

More preferred compounds of formula I include those wherein R¹ is

R⁶ is (C₁-C₆)alkyl and R³ is hydrogen; R² is phenyl or benzyl optionallysubstituted by chloro, fluoro, bromo, iodo, (C₁-C₆)alkyl ortrifluoromethyl; and R⁴ is hydrogen or (C₁-C₆)alkyl.

Specific preferred compounds of formula I include the following:

3,4-Dichloro-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;

4-Fluoro-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;

N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;

3,4-Dichloro-N-(1-methyl-2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;

3,4-Dichloro-N-(1-methyl-2-[2-(4-methylpiperazin-1-yl)-phenyl]-propyl)-benzamide;

3,4-Dichloro-N-methyl-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;

N-Benzyl-N-(2-[2-(4-methylpiperazin- 1-yl)-phenyl]-ethyl)-benzamide;

N-(4-chlorobenzyl)-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;

3,4-Dichloro-N-(2-{2-[methyl-(1-methylpyrolidin-2-ylmethyl)-amino]-phenyl}-ethyl)-benzamide;

3,4-Dichloro-N-{2-[2-(1-methyl-octahydro-pyrrolo[2,3-c]pyridin-6-yl)-phenyl]-ethyl}-benzamide;

3,4-Dichloro-N-{2-[2-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-phenyl]-ethyl}-benzamide;

3,4-Dichloro-N-{2-[2-(1-methylpiperidin-4-yl)-phenyl]-ethyl)-benzamide;

3,4-Dichloro-N-{2-[2-(2-dimethylaminoethoxy)-phenyl]-ethyl}-benzamide;

3,4-Dichloro-N-{2-[2-(2-dimethylamino-ethylsulfanyl)-phenyl]-ethyl}-benzamide;

3,4-Dichloro-N-{2-[2-(2-pyrrolidin-1-yiethoxy)-phenyl]-ethyl}-benzamide;

4-Chloro-N-{2-[2-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-benzamide;

4-Chloro-N-(2-{2-[methyl-(2-morpholin4-yl-ethyl)-amino]-phenyl}-ethyl)-benzamide;

2-(4-Chlorophenyl)-N-{2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl}-acetamide;

N-{2-[2-(4-Methylpiperazin-1-yl)-phenyl]-ethyl}-N-phenylacetamide;

N-{2-[2-(4-Methylpiperazin-1-yl)-phenyl]-ethyl}-isonicotinamide;

N-{2-[2-(1-Azabicyclo[2.2.2]oct-4-yl)-phenyl]-ethyl}-N-methylbenzamide;

N-{2-[2-(1,4-Dimethylpiperidin-4-yl)-phenyl]-ethyl}-4-fluorobenzamide;

4-Fluoro-N-{2-[2-(9-methyl-3,9-diazabicyclo[3.3.1]non-3-yl)-phenyl]-ethyl}-benzamide;

N-(2-[2-(1,4-Diazabicyclo[3.3.1]non-4-yl)-phenyl]-ethyl}-N-methylbenzamide;

N-{1-Methyl-2-[2-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-phenyl]-ethyl}-benzamide;

2,4-Dichloro-N-methyl-N-{1-methyl-2-[2-(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)-phenyl]ethyl}-benzamide;

N-{2-[2-(4-Methyl-octahydroquinoxalin-1-yl)-phenyl]-ethyl}-benzamide;

N-{2-[2-(1-Ethylpyrrolidin-2-ylmethoxy)-phenyl]-ethyl}-benzamide;

5-Phenyloxazole-2-carboxylicacid{2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl}-amide;

5-Phenylthiophene-2-carboxylicacid{2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl}-amide;

5-Methylthiophene-2-carboxylicacid{2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl}-amide;

4-Fluoronaphthalene-1-carboxylicacid{2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl}-amide;

5-Fluoro-1H-indole-2-carboxylicacid{2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-amide;

4-Chloro-N-{2-[2-(3,4,5-trimethylpiperazin-1-yl)-phenyl]-ethyl}-benzamide;

3,4-Dichloro-N-{2-[2-(2,4,5-trimethylpiperazin-1-yl)-phenyl]-ethyl}-benzamide;and

3,4-Dichloro-N-{2-[2-(2,4,6-trimethylpiperazin-1-yl)-phenyl]-ethyl}-benzamide.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition selected fromhypertension, depression, generalized anxiety disorder, phobias (e.g.,agoraphobia, social phobia and simple phobias), posttraumatic stresssyndrome, avoidant personality disorder, premature ejaculation, eatingdisorders (e.g., anorexia nervosa and bulimia nervosa), obesity,chemical dependencies (e.g., addictions to alcohol, cocaine, heroin,phenolbarbitol, nicotine and benzodiazepines), cluster headache,migraine, pain, Adzheimer's disease, obsessive-compulsive disorder,panic disorder, memory disorders (e.g., dementia, amnestic disorders,and age-related cognitive decline (ARCD)), Parkinson's diseases (e.g.,dementia in Parkinson's disease, neuroleptic-induced parkinsonism andtardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia),vasospasm (particularly in the cerebral vasculature), cerebellar ataxia,gastrointestinal tract disorders (involving changes in motility andsecretion), negative symptoms of schizophrenia, premenstrual syndrome,fibromyalgia syndrome, stress incontinence, Tourette syndrome,trichotillomania, kleptomania, male impotence, cancer (e.g. small celllung carcinoma), chronic paroxysmal hemicrania and headache (associatedwith vascular disorders) in a mammal, preferably a human, comprising anamount of a compound of the formula I or a pharmaceutically acceptablesalt thereof effective in treating or preventing such disorder orcondition and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition that can be treated orprevented by enhancing serotonergic neurotransmission in a mammal,preferably a human, comprising an amount of a compound of the formula I,or a pharmaceutically acceptable salt thereof, effective in treating orpreventing such disorder or condition and a pharmaceutically acceptablecarrier. Examples of such disorders and conditions are those enumeratedin the preceding paragraph.

The present invention also relates to a method for treating orpreventing a disorder or condition selected from hypertension,depression (e.g., depression in cancer patients, depression inParkinson's patients, postmyocardial infarction depression, subsyndromalsymptomatic depression, depression in infertile women, pediatricdepression, major depression, single episode depression, recurrentdepression, child abuse induced depression, and post partum depression),generalized anxiety disorder, phobias (e.g., agoraphobia, social phobiaand simple phobias), posttraumatic stress syndrome, avoidant personalitydisorder, premature ejaculation, eating disorders (e.g., anorexianervosa and bulimia nervosa), obesity, chemical dependencies (e.g.,addictions to alcohol, cocaine, heroin, phenolbarbitol, nicotine andbenzodiazepines), cluster headache, migraine, pain, Alzheimer's disease,obsessive-compulsive disorder, panic disorder, memory disorders (eg.,dementia, amnestic disorders, and age-related cognitive decline (ARCD)),Parkinson's diseases (e.g., dementia in Parkinson's disease,neuroleptic-induced parkinsonism and tardive dyskinesias), endocrinedisorders (e.g., hyperprolactinaemia), vasospasm (particularly in thecerebral vasculature), cerebellar ataxia, gastrointestinal tractdisorders (involving changes in motility and secretion), negativesymptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome,stress incontinence, Tourette syndrome, trichotillomania, kleptomania,male impotence, cancer, (e.g., small cell lung carcinoma), chronicparoxysmal hemicrania and headache (associated with vascular disorders)in a mammal, preferably a human, comprising administering to a mammal inneed of such treatment or prevention an amount of a compound of theformula I, or a pharmaceutically acceptable salt thereof, that iseffective in treating or preventing such disorder or condition.

The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, preferably ahuman, comprising administering to a mammal in need of such treatment orprevention an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingor preventing such disorder or condition.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition selected fromhypertension, depression (e.g., depression in cancer patients,depression in Parkinson's patients, postmyocardial infarctiondepression, subsyndromal symptomatic depression, depression in infertilewomen, pediatric depression, major depression, single episodedepression, recurrent depression, child abuse induced depression, andpost partum depression), generalized anxiety disorder, phobias (eg.,agoraphobia, social phobia and simple phobias), posttraumatic stresssyndrome, avoidant personality disorder, premature ejaculation, eatingdisorders (e.g., anorexia nervosa and bulimia nervosa), obesity,chemical dependencies (e.g., addictions to alcohol, cocaine, heroin,phenolbarbitol, nicotine and benzodiazepines), cluster headache,migraine, pain, Alzheimer's disease, obsessive-compulsive disorder,panic disorder, memory disorders (e, dementia, amnestic disorders, andage-related cognitive decline (ARCD)), Parkinson's diseases (e.g.,dementia in Parkinson's disease, neuroleptic-induced parkinsonism andtardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia),vasospasm (particularly in the cerebral vasculature), cerebellar ataxia,gastrointestinal tract disorders (involving changes in motility andsecretion), negative symptoms of schizophrenia, premenstrual syndrome,fibromyalgia syndrome, stress incontinence, Tourette syndrome,trichotillomania, kleptomania, male impotence, cancer (e.g. small celllung carcinoma), chronic paroxysmal hemicrania and headache (associatedwith vascular disorders) in a mammal, preferably a human, comprising aserotonin receptor antagonizing or agonizing effective amount of acompound of the formula I, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition that can be treated orprevented by enhancing serotonergic neurotransmission in a mammal,preferably a human, comprising a serotonin receptor antagonizing oragonizing effective amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present invention also relates to a method for treating orpreventing a disorder or condition selected from hypertension,depression (e.g., depression in cancer patients, depression inParkinson's patients, postmyocardial infarction depression, subsyndromalsymptomatic depression, depression in infertile women, pediatricdepression, major depression, single episode depression, recurrentdepression, child abuse induced depression, and post partum depression),generalized anxiety disorder, phobias (e.g., agoraphobia, social phobiaand simple phobias), posttraumatic stress syndrome, avoidant personalitydisorder, sexual dysfunction (eg., premature ejaculation), eatingdisorders (e.g., anorexia nervosa and bulimia nervosa), obesity,chemical dependencies (e.g., addictions to alcohol, cocaine, heroin,phenolbarbitol, nicotine and benzodiazepines), cluster headache,migraine, pain, Alzheimer's disease, obsessive-compulsive disorder,panic disorder, memory disorders (e.g., dementia, amnestic disorders,and age-related cognitive decline (ARCD)), Parkinson's diseases (e.g.,dementia in Parkinson's disease, neuroleptic-induced parkinsonism andtardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia),vasospasm (particularly in the cerebral vasculature), cerebellar ataxia,gastrointestinal tract disorders (involving changes in motility andsecretion), negative symptoms of schizophrenia, premenstrual syndrome,fibromyalgia syndrome, stress incontinence, Tourette syndrome,trichotillomania, kleptomania, male impotence, cancer (e.g., small celllung carcinoma), chronic paroxysmal hemicrania and headache (associatedwith vascular disorders) in a mammal, preferably a human, comprisingadministering to a mammal requiring such treatment or prevention aserotonin receptor antagonizing or agonizing effective amount of acompound of the formula I or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, preferably ahuman, comprising administering to a mammal requiring such treatment orprevention a serotonin receptor antagonizing or agonizing effectiveamount of a compound of the formula I or a pharmaceutically acceptablesalt thereof.

The present invention relates to a pharmaceutical composition fortreating or preventing a condition or disorder that can be treated orprevented by enhancing serotonergic neurotransmission in a mammal,preferably a human, comprising:

a) a pharmaceutically acceptable carrier;

b) a compound of the formula I or a pharmaceutically acceptable saltthereof; and

c) a 5-HT re-uptake inhibitor, preferably sertraline, or apharmaceutically acceptable salt thereof;

wherein the amount of the active compounds (i.e., the compound offormula I and the 5-HT re-uptake inhibitor) are such that thecombination is effective in treating or preventing such disorder orcondition.

The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, preferably ahuman, comprising administering to a mammal requiring such treatment orprevention:

a) a compound of the formula I, defined above, or a pharmaceuticallyacceptable salt thereof; and

b) a 5-HT re-uptake inhibitor, preferably sertraline, or apharmaceutically acceptable salt thereof;

wherein the amounts of the active compounds (i.e., the compound offormula I and the 5-HT re-uptake inhibitor) are such that thecombination is effective in treating or preventing such disorder orcondition.

The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, preferably ahuman, comprising administering to said mammal requiring such treatmentor prevention:

a) a 5-HT_(1A) antagonist or a pharmaceutically acceptable salt thereof;and

b) a 5-HT_(1D) antagonist of formula I or a pharmaceutically acceptablesalt thereof;

wherein the amounts of each active compound (i.e., the 5-HT_(1A)antagonist and the 5-HT_(1D) antagonist) are such that the combinationis effective in treating or preventing such disorder or condition.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition that can be treated orprevented by enhancing serotonergic neurotransmission in a mammal,preferably a human, comprising:

a) a 5-HT_(1A) antagonist or a pharmaceutically acceptable salt thereof;and

b) a 5-HT_(1D) antagonist of formula I or a pharmaceutically acceptablesalt thereof;

wherein the amounts of each active compound (i.e., the 5-HT_(1A)antagonist and the 5-HT_(1D) antagonist) are such that the combinationis effective in treating or preventing such disorder or condition.

The present invention also relates to a compound of the formula

wherein the dashed line represents an optional double bond;

R¹ is a group of the formua G¹, G², G³, G⁴, G⁵ or G⁶ depicted below:

 wherein the broken line indicates an optional double bond;

a is zero to eight;

m is 0, 1, 2, 3 or 4;

p is 1, 2 or 3;

D is oxygen, sulfur, SO, SO₂, or NR⁷;

E is oxygen, sulfur, SO or SO₂;

X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C₁-C₆)alkyl,hydroxy, trifluoromethyl, (C₁-C₆)alkoxy, —S(O)_(t)(C₁-C₆)alkyl wherein tis 0, 1 or 2, —CO₂R¹⁰ or —CONR¹¹R¹²;

R⁴ is hydrogen, (C₁-C₄alkyl or —(CH₂)_(q)—J wherein q is 0, 1, 2 or 3,and J is phenyl or naphthyl, wherein said phenyl or naphthyl may beoptionally substituted with one to three substituents independentlyselected from the group consisting of chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyano and—S(O)_(k)(C₁-C₆)alkyl wherein k is 0, 1 or 2;

R⁵ is hydrogen or (C₁-C₃)alkyl;

R⁶ is selected from the group consisting of hydrogen, (C₁-C₆)alkyloptionally substituted with (C₁-C₆)alkoxy or one to three fluorineatoms, or [(C₁-C₄)alkyl]aryl wherein the aryl moiety is phenyl,naphthyl, or heteroaryl-(CH₂)_(q)—, wherein the heteroaryl moiety isselected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl,benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one,two, three or four, and wherein said aryl and heteroaryl moieties mayoptionally be substituted with one or more substituents independentlyselected from the group consisting of chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyano and—SO_(g)(C₁-C₆)alkyl, wherein g is zero, one or two;

R⁷ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,[(C₁-C₄)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, orheteroaryl-(CH₂)_(r)—, wherein the heteroaryl moiety is selected fromthe group consisting of pyridyl, pyrimidyl, benzoxazolyl,benzothiazolyl, benzisoxazolyl and benzisothiazolyl and r is zero, one,two, three or four, and wherein said aryl and heteroaryl moieties mayoptionally be substituted with one or more substituents independentlyselected from the group consisting of chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, —C(═O)—(C₁-C₆)alkyl, cyanoand —SO_(j)(C₁-C₆)alkyl, wherein j is zero, one or two;

or R⁶ and R⁷ taken together form a 2 to 4 carbon chain;

R⁸ is hydrogen or (C₁-C₃)alkyl;

R⁹ is hydrogen or (C₁-C₆)alkyl;

or R⁶ and R⁹, together with the nitrogen atom to which they areattached, form a 5 to 7 membered heteroalkyl ring that may contain fromzero to four heteroatoms selected from nitrogen, sulfur and oxygen;

each of R¹⁰, R¹¹ and R¹² is selected, independently, from the radicalsset forth in the definition of R³; or R¹¹ and R¹², together with thenitrogen to which they are attached, form a 5 to 7 membered heteroalkylring that may contain from zero to four heteroatoms selected fromnitrogen, sulfur and oxygen; and

each R¹³ is, independently, (C₁-C₄)alkyl or a (C₁-C₄)methylene bridgefrom one of the ring carbons of the piperazine or piperidine ring of G¹or G², respectively, to the same or another ring carbon or a ringnitrogen of the piperazine or piperidine ring of G¹ or G², respectively,having an available bonding site, or to a ring carbon of R⁶ having anavailable bonding site;

R¹⁴ is amino or nitro;

with the proviso that when R¹⁴ is amino, the dashed line does notrepresent a double bond; and

with the proviso that when the broken line in formula G² is a doublebond, R⁸ is absent.

“Enhanced serotonergic neurotransmission,” as used herein, refers toincreasing or improving the neuronal process whereby serotonin isreleased by a pre-synaptic cell upon excitation and crosses the synapseto stimulate or inhibit the post-synaptic cell.

“Chemical dependency,” as used herein, means an abnormal craving ordesire for, or an addiction to a drug. Such drugs are generallyadministered to the affected individual by any of a variety of means ofadministration, including oral, parenteral, nasal or by inhalation.Examples of chemical dependencies treatable by the methods of thepresent invention are dependencies on alcohol, nicotine, cocaine,heroin, phenolbarbitol, and benzodiazepines (e.g., Valium (trademark)).“Treating a chemical dependency,” as used herein, means reducing oralleviating such dependency.

Sertraline,(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine,as used herein has the chemical formula C₁₇H₁₇NCl₂ and the followingstructural formula

Its synthesis is described in U.S. Pat. No. 4,536,518, assigned toPfizer Inc. Sertraline hydrochloride is useful as an antidepressant andanorectic agent, and is also useful in the treatment of depression,chemical dependencies, anxiety obsessive compulsive disorders, phobias,panic disorder, post traumatic stress disorder, and prematureejaculation.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated m, R¹,R², R³, R⁴, R⁵ and X in the reaction Schemes and the discussion thatfollow are defined as above.

Scheme 1 illustrates a method of synthesizing compounds of formula Iwherein R¹ is a group of the formula G¹ though G⁶ attached to anaromatic (e.g., phenyl) ring and R⁵ is H or (C₁ to C₃) alkyl. Referringto Scheme 1, a compound of the formula II is reacted with a nitroalkylcompound of the formula R⁴CH₂NO₂ in the presence of a base and in aorganic solvent to generate a nitroalkene of general formula III.Typically, the base employed is present as a salt, such as dimethylaminehydrochloride or ammonium acetate, as described by R. Royer inSynthesis, 1984, 12, 1054 or by H. Zhao et al in J. Med. Chem., 1997,40(8), 1186.

The intermediate nitroalkenes of formula III prepared as described abovecan then be converted to the alkylamines of general formula IV in one oftwo sequences. First, the carbon—carbon double bond of the nitroalkenemay be selectively reduced in the presence of the nitro group throughthe use of specific reduction conditions. Such conditions can involvethe use of selective reducing agents such as sodium borohydride orlithium borohydride at a temperature of about 0° C. to about 50° C. fora period of about 10 minutes to about 12 hours. Typically, the reductionis performed using methanol at 0° C. to 20° C., until the reaction isdetermined to be complete by thin-layer chromatography (tlc) or byinstrumental techniques such as ¹H-NMR or mass spectra. Representativeconditions are described in Synthetic Commun., 1985, 151.

The use of hydrogenation conditions (ref: R. E. Harmon, et al, J. Org.Chem., 1969, 34, 3684) in the presence of a homogeneous catalyst such aschlorotris-(triphenylphosphine)rhodium(l) (i.e., Wilkinson's catalyst)has also been reported to selectively reduce the carbon—carbon doublebond without reducing the nitro group.

The corresponding nitroalkyl intermediate thus prepared can subsequentlybe reduced to the compounds of general formula IV using reductiontechniques familiar to one skilled in the art. For example, suchintermediate nitroalkyl compounds can be reduced to the aminoalkylcompounds of formula IV using a metal, such as iron or zinc, in anacidic solvent such as acetic acid or aqueous hydrochloric acid attemperature of about 0° C. to about 50° C.

Alternatively, the intermediate of general formula III may be converteddirectly to the intermediate of general formula IV by the use of lessselective agents which are capable of reducing the carbon—carbon doublebond and the nitro group. Such reagents include metal hydrides, likelithium aluminum hydride (LAH) or sodium borohydride/borane, which havebeen used to perform similar conversions; LAH is preferred. Typicalsolvents for the reaction include ethers such as diethyl ether or THFand reaction temperatures from about 0° C. to about the boiling point ofthe solvent employed. Hydrogenation in the presence of a metal catalystsuch as Pd or Pt, in an inert solvent such as methanol, ethanol or ethylacetate at pressures of about one to about five atmospheres of hydrogenis also a method for this conversion.

The intermediates of general formula IV can then be converted to theamide compounds of general formula I (where R³=H) by reacting the formerwith an acid anhydride of formula (R²CO)—O—(COR¹⁴), or an acid halide offormula R²CO—A, wherein A is Cl, Br or I and R¹⁴ is, for example,hydrogen or R². This conversion is well documented in the literature;for example, see Vogel, Textbook of Practical Organic Chemistry, 4thed., Longman Group Ltd., London, 1978. This reaction is generallyconducted in a reaction inert solvent, optionally in the presence of anacid scavenger such as triethylamine (TEA), pyridine, Na₂CO₃, K₂CO₃ andthe like and at temperatures from about 0° C. to about the boiling pointof the solvent employed in the amide formation.

Alternatively, the acid halide of formula R²COA may be reacted with theamino compound of formula IV under Schotten-Baumann conditions in thepresence of a suitable base such as NaOH, in an aqueous medium and at aconvenient temperature of about 0° C. to about 100° C., typically atroom temperature, to prepare the amides of formula I (where R³=H).

In another method, an acid of formula R²COOH and the amine of formula IVmay be converted directly to the compounds of formula I (wherein R³=H)by means of a dehydrating reagent such as dicyclohexylcarbodiimide(DCC), diphenylphosphoryl azide (DPA) or1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (DEC) in a suitablereaction inert solvent such as tetrahydrofuran (THF) or diethyl ether asdescribed in Tetrahedron Letters, 1993, 34, 7685.

Finally, compounds of general formula I (where R³=H) can be converted tocompounds of general formula I (where R³≠H) by alkylation of the amidenitrogen using conditions and procedures well known to those skilled inthe art of organic synthesis. For example, treatment of the compounds offormula I (where R³=H) with a strong base such as sodium hydride,potassium hydride, sodium amide or lithium diisopropylamide (LDA) in areaction inert solvent such as benzene, N,N-dimethylformamide (DMF) orN,N-dimethylacetamide (DMA), THF and the like, at temperatures fromabout −80° to about 100° C. are typically useful in generating anintermediate amide anion. Preferred conditions are sodium hydride andDMF at 25° C. The anion can then be reacted with an alkylating reagentof the formula (R³)₂SO₄ or R³—L¹, where R³ is as previously defined andL¹ is a leaving group such as Cl, Br or I to produce the compound ofgeneral formula I.

Scheme 2 illustrates a method of synthesizing compounds of the formulaII, the starting materials of Scheme 1, wherein R¹ is a group of theformula G¹, G³, G⁴, G⁵ or G⁶. Referring to Scheme 2, a compound of theformula VII, wherein Q is a suitable leaving group (e.g., chloro,fluoro, bromo, mesylate, tosylate, etc.), is reacted with a compound ofthe formula R¹H, wherein H refers to a hydrogen atom on group D or E oron nitrogen atoms from G¹, G³, G⁵ or G⁶ and R¹ is a group of the formulaG¹, G³, G⁴, G⁵ or G⁶ in the presence of a base, to form thecorresponding compound of formula II. This reaction is generally carriedout at a temperature from about 0° C. to about 140° C., preferably atabout the reflux temperature, in a polar solvent such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide(DMA) or N-methyl-2-pyrrolidinone (NMP), preferably DMF. Suitable bases,when present, include anhydrous sodium carbonate (Na₂CO₃), potassiumcarbonate (K₂CO₃), sodium hydroxide (NaOH) and potassium hydroxide(KOH), as well as amines such as pyrrolidine, triethylamine andpyridine. Anhydrous potassium carbonate is preferred.

The starting materials of the formula VII are either commerciallyavailable or known in the art. For example, compounds of formula VII inwhich R⁵ is hydrogen are readily available from commercial sources ormay be prepared using procedures disclosed in the chemical literature.Compounds of the formula VII may also be prepared from the correspondingcarboxylic acids or esters, (i.e., formula VII) wherein R¹=OH orO-alkyl), which are commercially available. These acids or esters can bereduced to the corresponding alcohols of formula XIV, depicted below,wherein Q is defined as for formula II, using one or more of a varietyof reducing agents and conditions, depending upon the nature of thesubstituents Q and X.

Such reducing agents include sodium borohydride (NaBH₄), sodiumcyanoborohydride (NaCNBH₃), lithium aluminum hydride (LiAIH₄) and boranein THF (BH₃.THF) in solvents such as methanol, ethanol, THF, diethylether and dioxane. Oxidation of the alcohol of formula XIV to thecorresponding aldehyde of formula VII (R⁵=H) may be accomplished using aselective oxidizing agent such as Jones reagent (hydrogen chromate(H₂CrO₄)), pyridinium chlorochromate (PCC) or manganese dioxide (MnO₂).References for such conversions are readily available (e.g., K. B.Wiberg, Oxidation in Organic Chemistry, Part A, Academic Press Inc,N.Y., 69-72 (1965)).

The compounds of formula R¹H used in the preparation of intermediates ofthe formula VII are readily available or may be prepared using standardmethods of organic synthesis known to those skilled in the art andadapted from procedures disclosed in the chemical literature. Forexample, the preparation of compounds of the formula R¹H, wherein R¹ isG¹, may be accomplished using the following reaction sequence, beginningwith commercially available N-tert-butoxycarbonyl piperazine (XV):

Alkylation of the compound of formula XV with a compound of the formulaR⁶L² wherein L² is a leaving group, and is defined as Q is defined aboveand R⁶ is (C₁-C₆)alkyl, aryl-(C₁-C₄)alkyl wherein the aryl moiety isphenyl or naphthyl, or heteroaryl-(CH₂)_(q)—, wherein q is zero, one,two, three or four, and the heteroaryl moiety is selected from pyridyl,pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, andbenzisothiazolyl, in the presence of an acid scavenger (e.g., sodiumbicarbonate (NaHCO₃), potassium bicarbonate (KHCO₃), sodium carbonate(Na₂CO₃) or potassium carbonate (K₂CO₃)), in a polar solvent such asacetone at a temperature of about 10° C. to about the reflux temperatureof the solvent, will yield the intermediate of formula XVI. Removal ofthe tert-butoxycarbonyl group can be accomplished using acidicconditions, e.g., HBr in acetic acid or trifluoroacetic acid until thereaction is judged to be complete.

Compounds of the formula II, wherein R¹ is tetrahydropyridine orpiperidine (i.e. compounds of the formula G²) and R² is hydrogen, can beprepared from the compounds of formula VII, many of which arecommercially available, as depicted in Scheme 3. Referring to Scheme 3,the compound of formula VII is first converted into a protected aldehydeor ketone of the formula VII, wherein P represents the entire protectedaldehyde or ketone moiety, using methods well known in the art. Forexample, the 1,3-dioxolane derivative of the aldehyde may be preparedaccording to the method described by J. E. Cole et al., J. Chem. Soc.,244 (1962), by refluxing a solution of the aldehyde of formula VII and1,3-propanediol in anhydrous benzene with a catalytic amount ofp-toluenesulfonic acid. When R⁵ of formula VII is not hydrogen, theketone can be protected using an appropriate protecting group.Appropriate protecting groups can be chosen from many such groups basedon the presence and nature of the substituent X. Examples of suitableprotecting groups may be found in T. W. Greene and P. Wuts, ProtectingGroups in Organic Synthesis, John Wiley & Sons, 2nd Edition, New York,1991. The most preferred protecting groups are those that are resistantto catalytic hydrogenation (e.g., 1,3-dioxolane), which would thereforeallow for the subsequent reduction, if required, of the carbon—carbondouble bond of the tetrahydropyridines of formula IX.

Compounds of the formula VII can then be treated with vinylstannanes ofthe formula

for example, 1-BOC-4-trimethylstannyl-1,2,5,6-tetrahydropyridine(wherein BOC refers to tert-butyloxycarbonyl), in the presence of acatalyst, to form the corresponding compound of formula IX. Palladium isthe preferred catalyst (for example, ((C₆H₅)₃P)₄Pd or Pd₂(dba)₃),wherein dba refers to dibenzylidene acetone. Suitable solvents for thereaction include neat, acetonitrile, dimethylformamide,N-methyl-2-pyrrolidinone, preferably dimethylformamide. This reaction isconveniently run at about 20° C. to about 160° C., preferably about 60°C. to about 130° C. This reaction may be carried out as described in“Palladium-catalyzed Vinylation of Organic Halides” in OrganicReactions, 27, 345-390, (W. G. Dauben, Ed., John Wiley & Sons, Inc., NewYork, N.Y., 1982).

Compounds of the formula IX can be converted into compounds of theformula II, wherein R¹ is tetrahydropyridine by removal of the aldehydeor ketone protecting group. The protecting group for the aldehyde orketone, P, can be converted into the unprotected ketone or aldehyde ofthe formula —C(═O)R⁵ using one or more of the techniques described inGreene, for example, stirring a solution of the compound of formula IXin THF and 5% hydrochloric acid at room temperature for 20 hours.

Alternatively, compounds of formula IX can be converted into compoundsof the formula II, where R¹ is piperidine (G²), by catalytichydrogenation of the tetrahydropyridine of formula IX, from the previousparagraph, using standard methods known in the art, generally usingpalladium on carbon as the catalyst, to form the corresponding compoundsof formula X. This reaction is typically performed in an inert solvent,such as ethanol or ethyl acetate, either with or without a protic acidsuch as acetic acid or hydrochloric acid (HCl). Acetic acid ispreferred. The protecting groups on G² (e.g., BOC) can be removed usingone or more of the techniques described in Greene, referred to above,for example, stirring the compound of formula X in ethyl acetate and 3molar hydrochloric acid at about room temperature for about 30 minutes.The protecting group for the aldehyde or ketone, P, can be convertedinto the unprotected ketone or aldehyde II as described above.

Compounds of the formula VIII from reaction Scheme 3 may also be treatedwith alkyllithium reagents, for example n-butyllithium, sec-butyllithiumor tert-butyllithium, preferably n-butyllithium in an inert solvent, asshown in Scheme 4, to form the intermediate lithium anion of formulaXII. Suitable solvents for this reaction include, for example, ether ortetrahydrofuran, preferably tetrahydrofuran. Reaction temperatures canrange from about −110° C. to about 0° C. The intermediate lithium anionsof formula XII can then be further reacted with a suitable electrophile,selection of which depends on the presence and nature of the substituentX. Suitable electrophiles for use in preparing compounds of the formulaII wherein R¹ is a group of the formula G² include, for example,carbonyl derivatives or alkylating agents (es., 1-BOC-4-piperidone). Inthe case where an aldehyde or ketone is used as the electrophile, thehydroxy group must be removed from the intermediate of formula XVIII, asdepicted below, in order to form the corresponding compound of formulaII.

This step may be accomplished by one of several standard methods knownin the art. For example, a thiocarbonyl derivative such as a xanthatemay be prepared and removed by free radical processes, both of which areknown to those skilled in the art. Alternatively, the hydroxyl group maybe removed by reduction with a hydride source such as triethysilaneunder acidic conditions, using, for example, trifluoroacetic acid orboron trifluoride. The reduction reaction can be performed neat or in asolvent such as methylene chloride. A further alternative would be tofirst convert the hydroxyl group to a suitable leaving group, such astosylate or chloride, using standard methods known in the art, and thento remove the leaving group with a nucleophilic hydride, such as, forexample, lithium aluminum hydride. The latter reaction is typicallyperformed in an inert solvent such as ether or tetrahydrofuran. Also, areducing agent may be used to reductively remove the benzylicsubstituent. Suitable reducing agents include, for example, Raney nickelin ethanol and sodium or lithium in liquid ammonia. Another alternativemethod for removing the hydroxyl group is to first dehydrate the alcoholof formula XVIII to an olefin of the formula IX (i.e. see Scheme 3) witha reagent such as Burgess salt (J. Org. Chem., 38, 26 (1973)) and thento catalytically hydrogenate the double bond under standard conditionswith a catalyst such as palladium on carbon. The alcohol may also bedehydrated to the olefin by treatment with acids such asp-toluenesulfonic acid.

Compounds of the formula II, wherein R¹ is G² and R⁶ is hydrogen, can beconverted into the corresponding compounds of the formula II, wherein R¹is G² and R⁶ is other than hydrogen, by reacting them with a compound ofthe formula R⁶L², as described above for preparing compounds of theformula XVI.

Unless indicated otherwise, the pressure of each of the above reactionsis not critical. Generally, the reactions will be conducted at apressure of about one to about three atmospheres, preferably at ambientpressure (about one atmosphere).

The compounds of the formula I which are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula I which are also acidic in nature, e.g.,where R² includes a COOH or tetrazole moiety, are capable of formingbase salts with various pharmacologically acceptable cations. Examplesof such salts include the alkali metal or alkaline-earth metal salts andparticularly, the sodium and potassium salts. These salts are allprepared by conventional techniques. The chemical bases which are usedas reagents to prepare the pharmaceutically acceptable base salts ofthis invention are those which form non-toxic base salts with the hereindescribed acidic compounds of formula I. These non-toxic base saltsinclude those derived from such pharmacologically acceptable cations assodium, potassium, calcium and magnesium, etc. These salts can easily beprepared by treating the corresponding acidic compounds with an aqueoussolution containing the desired pharmacologically acceptable cations,and then evaporating the resulting solution to dryness, preferably underreduced pressure. Alternatively, they may also be prepared by mixinglower alkanolic solutions of the acidic compounds and the desired alkalimetal alkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents are preferably employed in order to ensurecompleteness of reaction and maximum product yields.

Compounds of the formula I and their pharmaceutically acceptable salts(hereinafter also referred to, collectively, as “the active compounds”)are useful psychotherapeutics and are potent agonists and/or antagonistsof the serotonin 1A (5-HT_(1A)) and/or serotonin 1D (5-HT_(1D))receptors. The active compounds are useful in the treatment ofhypertension, depression, generalized anxiety disorder, phobias (e.g.,agoraphobia, social phobia and simple phobias), posttraumatic stresssyndrome, avoidant personality disorder, sexual dysfunction (e.g.,premature ejaculation), eating disorders (e.g., anorexia nervosa andbulimia nervosa), obesity, chemical dependencies (e.g., addictions toalcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepines),cluster headache, migraine, pain, Alzheimer's disease,obsessive-compulsive disorder, panic disorder, memory disorders (e.g.,dementia, amnestic disorders, and age-related cognitive decline (ARCD)),Parkinson's diseases (e.g., dementia in Parkinson's disease,neuroleptic-induced parkinsonism and tardive dyskinesias), endocrinedisorders (e.g., hyperprolactinaemia), vasospasm (particularly in thecerebral vasculature), cerebellar ataxia, gastrointestinal tractdisorders (involving changes in motility and secretion), negativesymptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome,stress incontinence, Tourette syndrome, trichotillomania, kleptomania,male impotence, cancer (e.g. small cell lung carcinoma), chronicparoxysmal hemicrania and headache (associated with vascular disorders).

The affinities of the compounds of this invention for the variousserotonin-1 receptors can be determined using standard radioligandbinding assays as described in the literature. The 5-HT_(1A) affinitycan be measured using the procedure of Hoyer et al. (Brain Res., 376, 85(1986)). The 5-HT_(1D) affinity can be measured using the procedure ofHeuring and Peroutka (J. Neurosci., 7, 894 (1987)).

The in vitro activity of the compounds of the present invention at the5-HT_(1D) binding site may be determined according to the followingprocedure. Bovine caudate tissue is homogenized and suspended in 20volumes of a buffer containing 50 mM TRiS•hydrochloride(tris[hydroxymethyl]aminomethane hydrochloride) at a pH of 7.7. Thehomogenate is then centrifuged at 45,000 G for 10 minutes. Thesupernatant is then discarded and the resulting pellet resuspended inapproximately 20 volumes of 50 mM TRIS•hydrochloride buffer at pH 7.7.This suspension is then pre-incubated for 15 minutes at 37° C., afterwhich the suspension is centrifuged again at 45,000 G for 10 minutes andthe supernatant discarded. The resulting pellet (approximately 1 gram)is resuspended in 150 ml of a buffer of 15 mM TRIS•hydrochloridecontaining 0.01 percent ascorbic acid with a final pH of 7.7 and alsocontaining 10 μM pargyline and 4 mM calcium chloride (CaCl₂). Thesuspension is kept on ice at least 30 minutes prior to use.

The inhibitor, control or vehicle is then incubated according to thefollowing procedure. To 50 μl of a 20 percent dimethylsulfoxide(DMSO)/80 percent distilled water solution is added 200 μl of tritiated5-hydroxytryptamine (2 nM) in a buffer of 50 mM TRIS•hydrochloridecontaining 0.01 percent ascorbic acid at pH 7.7 and also containing 10gM pargyline and 4 μM calcium chloride, plus 100 μM of 8-hydroxy-DPAT(dipropylaminotetraline) and 100 nM of mesulergine. To this mixture isadded 750 μl of bovine caudate tissue, and the resulting suspension isvortexed to ensure a homogenous suspension. The suspension is thenincubated in a shaking water bath for 30 minutes at 25° C. Afterincubation is complete, the suspension is filtered using glass fiberfilters (e.g., Whatman GF/B-filters™). The pellet is then washed threetimes with 4 ml of a buffer of 50 mM TRIS•hydrochloride at pH 7.7. Thepellet is then placed in a scintillation vial with 5 ml of scintillationfluid (aquasol 2™) and allowed to sit overnight. The percent inhibitioncan be calculated for each dose of the compound. An IC₅₀ value can thenbe calculated from the percent inhibition values.

The activity of the compounds of the present invention for 5-HT_(1A)binding ability can be determined according to the following procedure.Rat brain cortex tissue is homogenized and divided into samples of 1gram lots and diluted with 10 volumes of 0.32 M sucrose solution. Thesuspension is then centrifuged at 900 G for 10 minutes and the supernateseparated and recentrifuged at 70,000 G for 15 minutes. The supernate isdiscarded and the pellet re-suspended in 10 volumes of 15 mMTRIS•hydrochloride at pH 7.5. The suspension is allowed to incubate for15 minutes at 37° C. After pre-incubation is complete, the suspension iscentrifuged at 70,000 G for 15 minutes and the supernate discarded. Theresulting tissue pellet is resuspended in a buffer of 50 mMTRIS•hydrochloride at pH 7.7 containing 4 mM of calcium chloride and0.01 percent ascorbic acid. The tissue is stored at −70° C. until readyfor an experiment. The tissue can be thawed immediately prior to use,diluted with 10 μm pargyline and kept on ice.

The tissue is then incubated according to the following procedure. Fiftymicroliters of control, inhibitor, or vehicle (1 percent DMSO finalconcentration) is prepared at various dosages. To this solution is added200 μl of tritiated 8-hydroxy DPAT at a concentration of 1.5 nM in abuffer of 50 mM TRIS•hydrochloride at pH 7.7 containing 4 mM calciumchloride, 0.01 percent ascorbic acid and pargyline. To this solution isthen added 750 μl of tissue and the resulting suspension is vortexed toensure homogeneity. The suspension is then incubated in a shaking waterbath for 30 minutes at 37° C. The solution is then filtered, washedtwice with 4 ml of 10 mM TRISehydrochloride at pH 7.5 containing 154 mMof sodium chloride. The percent inhibition is calculated for each doseof the compound, control or vehicle. IC₅₀ values are calculated from thepercent inhibition values.

The compounds of formula I of the present invention described in thefollowing Examples were assayed for 5-HT_(1A) and 5-HT_(1D) affinityusing the aforementioned procedures. All such compounds of the inventionthat were tested exhibited IC₅₀'s less than 0.60 μM for 5-HT_(1D)affinity and IC₅₀'s less than 1.0 μM for 5-HT_(1A) affinity.

The agonist and antagonist activities of the compounds of the inventionat 5-HT_(1A) and 5-HT_(1D) receptors can be determined using a singlesaturating concentration according to the following procedure. MaleHartley guinea pigs are decapitated and 5-HT_(1A) receptors aredissected out of the hippocampus, while 5-HT_(1D) receptors are obtainedby slicing at 350 mm on a Mcllwain tissue chopper and dissecting out thesubstantia nigra from the appropriate slices. The individual tissues arehomogenized in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using ahand-held glass-Teflon) homogenizer and centrifuged at 35,000×g for 10minutes at 4° C. The pellets are resuspended in 100 mM HEPES buffercontaining 1 mM EGTA (pH 7.5) to a final protein concentration of 20 mg(hippocampus) or 5 mg (substantia nigra) of protein per tube. Thefollowing agents are added so that the reaction mix in each tubecontains 2.0 mM MgCl₂, 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mMphosphocreatine, 0.31 mg/mL creatine phosphokinase, 100 μM GTP and 0.5-1microcuries of [³²P]-ATP (30 Ci/mmol: NEG-003—New England Nuclear).Incubation is initiated by the addition of tissue to siliconizedmicrofuge tubes (in triplicate) at 30° C. for 15 minutes. Each tubereceives 20 μL tissue, 10 μL drug or buffer (at 10×final concentration),10 μL 32 nM agonist or buffer (at 10×final concentration), 20 μLforskolin (3 μM final concentration) and 40 μL of the preceding reactionmix. Incubation is terminated by the addition of 100 μL 2% SDS, 1.3 mMcAMP, 45 mM ATP solution containing 40,000 dpm [³H]-cAMP (30 Ci/mmol:NET-275—New England Nuclear) to monitor the recovery of cAMP from thecolumns. The separation of [³²P]-ATP and [³²P]-cAMP is accomplishedusing the method of Salomon et al., Analytical Biochemistry, 1974, 58,541-548. Radioactivity is quantified by liquid scintillation counting.Maximal inhibition is defined by 10 μM (R)-8-OH-DPAT for 5-HT_(1A)receptors, and 320 nM 5-HT for 5-HT_(1D) receptors. Percent inhibitionsby the test compounds are then calculated in relation to the inhibitoryeffect of (R)-8-OH-DPAT for 5-HT_(1A) receptors or 5-HT for 5-HT₁receptors. The reversal of agonist induced inhibition offorskolin-stimulated adenylate cyclase activity is calculated inrelation to the 32 nM agonist effect.

The compounds of the invention can be tested for in vivo activity forantagonism of 5-HT_(1D) agonist-induced hypothermia in guinea pigsaccording to the following procedure.

Male Hartley guinea pigs from Charles River, weighing 250-275 grams onarrival and 300-600 grams at testing, serve as subjects in theexperiment. The guinea pigs are housed under standard laboratoryconditions on a 7 a.m. to 7 p.m. lighting schedule for at least sevendays prior to experimentation. Food and water are available ad libitumuntil the time of testing.

The compounds of the invention can be administered as solutions in avolume of 1 ml/kg. The vehicle used is varied depending on compoundsolubility. Test compounds are typically administered either sixtyminutes orally (p.o.) or 0 minutes subcutaneously (s.c.) prior to a5-HT_(1D) agonist, such as [3-(1-methylpyrrolidin-2-ylmethyl)-1H-indol-5-yl]-(3-nitropyridin-3-yl)-amine, which can be prepared asdescribed in PCT publication WO93/111 06, published Jun. 10, 1993 andwhich is administered at a dose of 5.6 mg/kg, s.c. Before a firsttemperature reading is taken, each guinea pig is placed in a clearplastic shoe box containing wood chips and a metal grid floor andallowed to acclimate to the surroundings for 30 minutes. Animals arethen returned to the same shoe box after each temperature reading. Priorto each temperature measurement each animal is firmly held with one handfor a 30-second period. A digital thermometer with a small animal probeis used for temperature measurements. The probe is made of semi-flexiblenylon with an epoxy tip. The temperature probe is inserted 6 cm. intothe rectum and held there for 30 seconds or until a stable recording isobtained. Temperatures are then recorded.

In p.o. screening experiments, a “pre-drug” baseline temperature readingis made at −90 minutes, the test compound is given at −60 minutes and anadditional −30 minute reading is taken. The 5-HT_(1D) agonist is thenadministered at 0 minutes and temperatures are taken 30, 60, 120 and 240minutes later.

In subcutaneous screening experiments, a pre-drug baseline temperaturereading is made at −30 minutes. The test compound and 5-HT_(1D) agonistsare given concurrently and temperatures are taken at 30, 60, 120 and 240minutes later.

Data are analyzed with two-way analysis of variants with repeatedmeasures in Newman-Keuls post hoc analysis.

The active compounds of the invention can be evaluated as anti-migraineagents by testing the extent to which they mimic sumatriptan incontracting the dog isolated saphenous vein strip [P. P. A. Humphrey etal., Br. J. Pharmacol., 94, 1128 (1988)]. This effect can be blocked bymethiothepin, a known serotonin antagonist. Sumatriptan is known to beuseful in the treatment of migraine and produces a selective increase incarotid vascular resistance in the anesthetized dog. The pharmacologicalbasis of sumatriptan efficacy has been discussed in W. Fenwick et al.,Br. J. Pharmacol., 96, 83 (1989).

The serotonin 5-HT₁ agonist activity can be determined by the in vitroreceptor binding assays, as described for the 5-HT_(1A) receptor usingrat cortex as the receptor source and [³H]-8-OH-DPAT as the radioligand[D. Hoyer et al. Eur. J. Pharm., 118, 13 (1985)] and as described forthe 5-HT_(1D) receptor using bovine caudate as the receptor source and[³H]serotonin as the radioligand [R. E. Heuring and S. J. Peroutka, J.Neuroscience, 7, 894 (1987)]. Of the active compounds tested, allexhibited an IC₅₀ in either assay of 1 μM or less.

The compounds of formula I may advantageously be used in conjunctionwith one or more other therapeutic agents, for instance, differentantidepressant agents such as tricyclic antidepressants (e.g.,amitriptyline, dothiepin, doxepin, trimipramine, butripyline,clomipramine, desipramine, imipramine, iprindole, lofepramine,nortriptyline or protriptyline), monoamine oxidase inhibitors (e.g.,isocarboxazid, phenelzine or tranylcyclopramine) or 5-HT re-uptakeinhibitors (e.g., fluvoxamine, sertraline, fluoxetine or paroxetine),and/or with antiparkinsonian agents such as dopaminergicantiparkinsonian agents (e.g., levodopa, preferably in combination witha peripheral decarboxylase inhibitor e.g., benserazide or carbidopa, orwith a dopamine agonist e.g., bromocriptine, lysuride or pergolide). Itis to be understood that the present invention covers the use of acompound of general formula (I) or a physiologically acceptable salt orsolvate thereof in combination with one or more other therapeuticagents.

Compounds of the formula I and the pharmaceutically acceptable saltsthereof, in combination with a 5-HT re-uptake inhibitor (e.g.,fluvoxamine, sertraline, fluoxetine or paroxetine), preferablysertraline, or a pharmaceutically acceptable salt or polymorph thereof(the combination of a compound of formula I with a 5-HT re-uptakeinhibitor is referred herein to as “the active combination”), are usefulpsychotherapeutics and may be used in the treatment or prevention ofdisorders the treatment or prevention of which is facilitated byenhanced serotonergic neurotransmission (e.g., hypertension, depression,generalized anxiety disorder, phobias, posttraumatic stress syndrome,avoidant personality disorder, sexual dysfunction, eating disorders,obesity, chemical dependencies, cluster headache, migraine, pain,Alzheimer's disease, obsessive-compulsive disorder, panic disorder,memory disorders (e.g., dementia, amnestic disorders, and age-associatedmemory impairment), Parkinson's diseases (e.g., dementia in Parkinson'sdisease, neuroleptic-induced Parkinsonism and tardive dyskinesias),endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularlyin the cerebral vasculature), cerebellar ataxia, gastrointestinal tractdisorders (involving changes in motility and secretion) chronicparoxysmal hemicrania and headache (associated with vascular disorders).

Serotonin (5-HT) re-uptake inhibitors, preferably sertraline, exhibitpositive activity against depression; chemical dependencies; anxietydisorders including panic disorder, generalized anxiety disorder,agoraphobia, simple phobias, social phobia, and post-traumatic stressdisorder; obsessive-compulsive disorder; avoidant personality disorderand premature ejaculation in mammals, including humans, due in part totheir ability to block the synaptosomal uptake of serotonin.

U.S. Pat. No. 4,536,518 describes the synthesis, pharmaceuticalcomposition and use of sertraline for depression and is herebyincorporated by reference in its entirety.

Activity of the active combination as antidepressants and relatedpharmacological properties can be determined by methods (1)-(4) below,which are described in Koe, B. et al., Journal of Pharmacology andExperimental Therapeutics, 226 (3), 686-700 (1983). Specifically,activity can be determined by studying (1) their ability to affect theefforts of mice to escape from a swim-tank (Porsolt mouse “behaviordespair” test), (2) their ability to potentiate5-hydroxytryptophan-induced behavioral symptoms in mice in vivo, (3)their ability to antagonize the serotonin-depleting activity ofp-chloroamphetamine hydrochloride in rat brain in vivo, and (4) theirability to block the uptake of serotonin, norepinephrine and dopamine bysynaptosomal rat brain cells in vitro. The ability of the activecombination to counteract reserpine hypothermia in mice in vivo can bedetermined according to the methods described in U.S. Pat. No.4,029,731.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, eg., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., depression) is 0.1to 200 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to above(e.g., migraine) in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains 20 μg to 1000 μg ofthe compound of the invention. The overall daily dose with an aerosolwill be within the range 100 μg to 10 mg. Administration may be severaltimes daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or3 doses each time.

In connection with the use of an active compound of this invention witha 5-HT re-uptake inhibitor, preferably sertraline, for the treatment ofsubjects possessing any of the above conditions, it is to be noted thatthese compounds may be administered either alone or in combination withpharmaceutically acceptable carriers by either of the routes previouslyindicated, and that such administration can be carried out in bothsingle and multiple dosages. More particularly, the active combinationcan be administered in a wide variety of different dosage forms, i.e.,they may be combined with various pharmaceutically-acceptable inertcarriers in the form of tablets, capsules, lozenges, troches, hardcandies, powders, sprays, aqueous suspension, injectable solutions,elixirs, syrups, and the like. Such carriers include solid diluents orfillers, sterile aqueous media and various non-toxic organic solvents,etc. Moreover, such oral pharmaceutical formulations can be suitablysweetened and/or flavored by means of various agents of the typecommonly employed for such purposes. In general, the compounds offormula I are present in such dosage forms at concentration levelsranging from about 0.5% to about 90% by weight of the total composition,i.e., in amounts which are sufficient to provide the desired unit dosageand a 5-HT re-uptake inhibitor, preferably sertraline, is present insuch dosage forms at concentration levels ranging from about 0.5% toabout 90% by weight of the total composition, i.e., in amounts which aresufficient to provide the desired unit dosage.

A proposed daily dose of an active compound of this invention in thecombination formulation (a formulation containing an active compound ofthis invention and a 5-HT re-uptake inhibitor) for oral, parenteral,rectal or buccal administration to the average adult human for thetreatment of the conditions referred to above is from about 0.01 mg toabout 2000 mg, preferably from about 0.1 mg to about 200 mg of theactive ingredient of formula I per unit dose which could beadministered, for example, 1 to 4 times per day.

A proposed daily dose of a 5-HT re-uptake inhibitor, preferablysertraline, in the combination formulation for oral, parenteral orbuccal administration to the average adult human for the treatment ofthe conditions referred to above is from about 0.1 mg to about 2000 mg,preferably from about 1 mg to about 200 mg of the 5-HT re-uptakeinhibitor per unit dose which could be administered, for example, 1 to 4times per day.

A preferred dose ratio of sertraline to an active compound of thisinvention in the combination formulation for oral, parenteral or buccaladministration to the average adult human for the treatment of theconditions referred to above is from about 0.00005 to about 20,000,preferably from about 0.25 to about 2,000.

Aerosol combination formulations for treatment of the conditionsreferred to above in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains from about 0.01 μgto about 100 mg of the active compound of this invention, preferablyfrom about 1 μg to about 10 mg of such compound. Administration may beseveral times daily, for example 2, 3, 4 or 8 times, giving for example,1, 2 or 3 doses each time.

Aerosol formulations for treatment of the conditions referred to abovein the average adult human are preferably arranged so that each metereddose or “puff” of aerosol contains from about 0.01 mg to about 2000 mgof a 5-HT re-uptake inhibitor, preferably sertraline, preferably fromabout 1 mg to about 200 mg of sertraline. Administration may be severaltimes daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or3 doses each time.

As previously indicated, a 5-HT re-uptake inhibitor, preferablysertraline, in combination with compounds of formula I are readilyadapted to therapeutic use as antidepressant agents. In general, theseantidepressant compositions containing a 5-HT re-uptake inhibitor,preferably sertraline, and a compound of formula I are normallyadministered in dosages ranging from about 0.01 mg to about 100 mg perkg of body weight per day of a 5-HT re-uptake inhibitor, preferablysertraline, preferably from about 0.1 mg. to about 10 mg per kg of bodyweight per day of sertraline; with from about 0.001 mg. to about 100 mgper kg of body weight per day of a compound of formula I, preferablyfrom about 0.01 mg to about 10 mg per kg of body weight per day of acompound of formula I, although variations will necessarily occurdepending upon the conditions of the subject being treated and theparticular route of administration chosen.

The following Examples illustrate the preparation of the compounds ofthe present invention. Melting points are uncorrected. NMR data arereported in parts per million (8) and are referenced to the deuteriumlock signal from the sample solvent (deuteriochloroform unless otherwisespecified). Specific rotations were measured at room temperature usingthe sodium D line (589 nm). Commercial reagents were utilized withoutfurther purification. THF refers to tetrahydrofuran. DMF refers toN,N-dimethylformamide. Chromatography refers to column chromatographyperformed using 32-63 μm silica gel and executed under nitrogen pressure(flash chromatography) conditions. Room or ambient temperature refers to20-25° C. All non-aqueous reactions were run under a nitrogen atmospherefor convenience and to maximize yields Concentration at reduced pressuremeans that a rotary evaporator was used.

PREPARATION 1 2-[2-(4-methylpiperazin-1-yl)phenyl]-ethylamine

A mixture of 2-(4-methylpiperazin-1-yl)benzaldehyde (5 grams, 24.5 mmol,prepared according to the method of D. Reinhoudt et al., Synthesis,1987, 641), dimethylamine hydrochoride (4 grams, 49 mmol), potassiumfluoride (0.213 grams, 3.7 mmol) and nitromethane (100 mL) in anhydroustoluene (100 mL) was refluxed under nitrogen using a Dean Stark trap tocollect the azeotroped water. After 2 hour the reaction was determinedto be completed by thin layer chromatography using triethylamine:methanol: ethyl acetate (5:10:85). The solvents were removed in vacuoand the residue was partitioned between methylene chloride and saturatedaqueous sodium carbonate. The organic layer was then washed withsaturated sodium chloride, dried and concentrated to a red oil, 5.69grams. Chromatography using silica gel on a 4×1.75 inch column, elutingwith 100% ethyl acetate followed by increasing percentages of methanol,produced 4.03 grams of 1-methyl-4-[2-(2-nitrovinyl)-phenyl]-piperazineas a light orange solid. ¹H-nmr (CDCl₃, 400 MHz) δ 8.35 (1H, d, J=13.9Hz), 7.66 (1H, d, J=13.7 Hz), 7.46 (2H, m), 7.10 (2H, m), 2.99 (4H, m),2.63 (4H, m), 2.38 (3H, s).

A slurry of sodium borohydride (0.395 grams, 10.43 mmol) in 30 mLtetrahydrofuran and 30 mL methanol, cooled to 0° C., was treated with2.57 grams (10.43 mmol) of the preceding compound and allowed to stir atroom temperature for 60 hours. The solvents were removed in vacuo, theresidue was partitioned between methylene chloride and water, theorganic layer was washed with saturated aqueous sodium chloride, driedand concentrated to a brown foam, 2.06 grams. Flash chromatography on4.3 grams of silica gel, eluting with 300 mL of methanol: ethyl acetate(1:99) followed by 400 mL of triethylamine: methanol:ethyl acetate(1:3:96) produced 0.355 grams of1-methyl-4-[2-(2-nitroethyl)-phenyl]-piperazine as a yellow oil whichslowly solidified. ¹H-nmr (CDCl₃, 400 MHz) δ 7.07-7.27 (4H, m), 4.67(2H, t), 3.34 (2H, t), 2.90 (4H, m), 2.57 (4H, m), 2.35 (3H, s). Massspectrum: 250 (m⁺¹).

A mixture of the above nitroethyl intermediate (0.200 grams, 0.803 mmol)and iron filings (0.900 grams, 16 mmol) in 5.0 mL of acetic acid wasrefluxed for 1.5 hours. After cooling to room temperature, the mixturewas evaported in vacuo and the residue was partitioned between methylenechloride and 1 N sodium hydroxide. The organic layer was separated andwashed several times with saturated aqueous sodium chloride, dried andconcentrated in vacuo to produce2-[2-(4-methylpiperazin-1-yl)phenyl]-ethylamine as a tan oil, 0.108grams. Mass spectrum: 220 (m⁺¹).

PREPARATION 2 2-[2-(4-methylpiperazin-1-yl)phenyl]-ethylamine

Under nitrogen in a 200 mL flask, lithium aluminum hydride (1.6 g, 42.2mmol) was added portionwise to 60 mL of anhydrous diethyl ether. To thiswas added a solution of 1-methyl-4[2-nitrovinyl)-phenyl]-piperazine (3.7grams, 15 mmol), prepared according to Preparation 1, in 40 mL oftetrahydrofuran (THF) over a 30 minute period so as to control thevigorous evolution of hydrogen gas. The resulting light tan suspensionwas stirred for 36 hours at room temperature. The reaction was worked upby cautiously adding 2 ml of water, 4 mL of 15% aqueous sodiumhydroxide, 6 mL of water and stirring for an additional 1 hour. Themixture was filtered through d.e. and concentrated to give the titleproduct as a dark amber colored oil, 3.01 grams. ¹H-nmr (DMSO-d₆, 300MHz) d 7.20-6.97 (m, 4H), 2.82-2.77 (m, 7H), 2.72-2.67 (m, 2H), 2.47 (brm, 5H), 2.23 (s, 3H). ¹³C-nmr (DMSO-d₆, 300 MHz) 151.6, 135.3, 129.7,126.7, 123.6, 119.9, 55.3, 52.3, 45.9, 42.8, 34.8 ppm. Mass spectrum:220 (m⁺¹, 75%), 203 (m⁺¹—NH3, 100%).

EXAMPLE 13,4-dichloro-N-(2-[2-(4-methylpiperazin-1-yl)phenyl]-ethyl)-benzamidehydrochloride monohydrate

A mixture of 2-[2-(4-methylpiperazin-1-yl)phenyl]-ethylamine (0.107grams, 0.49 mmol) and triethylamine (TEA, 88 mL, 0.64 mmol) in 6 mL ofanhydrous tetrahydrofuran (THF) was treated with 3,4-dichlorobenzoylchloride (0.113 grams, 0.53 mmol) and stirred overnight at roomtemperature. A thin-layer chromatography (tlc, silica gel) eluted withtriethylamine:methanol:ethyl acetate (5:10:85) indicated a new productformed with Rf of approximately 0.5. The solvent was removed undervacuum on a rotary evaporator and the residue was partitioned betweenmethylene chloride and saturated aqueous sodium carbonate, the organiclayer was washed with saturated sodium chloride, dried over magnesiumsulfate and concentrated in vacuo to a brown foam, 0.175 grams. The foamwas absorbed onto silica gel and flash chromatographed, eluting withethyl acetate:hexanes (50:50) followed by increasing percentages ofethyl acetate and triethylamine to obtain the crude product as a tanfoam, 0.94 mg. This was converted to the hydrochloride salt using 4.0molar hydrochloric acid in 1,4-dioxane. Recrystallization fromisopropanol produced a light tan solid, m.p. 110-120° C. ¹H-nmr (400MHz, d₆-DMSO) δ 610.45 (1H, br s), 8.94 (1H, t, J=5 Hz), 8.07 (1 H, t,J=2 hz), 7.83 (1H, t, J=2 Hz), 7.81 (1H, t, J=2 Hz), 7.74 (1H, d, J=2.1Hz), 3.53-3.40 (2H, m), 3.19-3.00 (4H, m), 2.90-2.80 (5H, m). Massspectrum (APCl): 392 (m⁺¹). Elemental analysis calculated forC₂₀H₂₃N₃OCl₂.HCl.H₂O: C, 53.76; H, 5.87; N, 9.40. Found: C, 54.05; H,5.62; N, 9.26.

The title compounds of examples 2-4 were prepared by method analogous tothat described in Example 1.

EXAMPLE 2 Thiophene-2-carboxylic acid{2-[2-(4-methylpiperazin-1-yl)-phenyl]ethyl}amide hydrochloride hydrate

Melting point: 236-238° C. Mass spectrum (APCl⁺): 330 (m⁺¹, 100%).Elemental analysis calculated for C₁₈H₂₃N₃OS.HCl.0.25 H₂O: C, 58.36, H,6.67, N 11.34. Found: C, 58.57, H, 6.72, N, 11.24.

EXAMPLE 34-methoxy-N-{2-[2-(4-methylpiperazin-1-yl)-phenyl]ethyl}-benzamide

Mass spectrum (APCl+): 338 (m⁺¹)

EXAMPLE 42,6-difluoro-N-{2-[2-(4-methylpiperazin-1-yl)-phenyl]ethyl]-benzamide

Mass spectrum (APCl+): 360 (m⁺¹)

What is claimed is:
 1. A pharmaceutical composition for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, comprising: a) apharmaceutically acceptable carrier; b) a compound of the formula

 or the pharmaceutically acceptable salt thereof, wherein R¹ is a groupof the formula G¹, G², G³, G⁴, G⁵ or G⁶ depicted below:

 wherein the broken line indicates an optional double bond; a is zero toeight; m is 0, 1, 2, 3 or 4; p is 1, 2 or 3; D is oxygen, sulfur, SO,SO₂, or NR⁷; E is oxygen, sulfur, SO or SO₂; X is hydrogen, chloro,fluoro, bromo, iodoi cyano, (C₁-C₆)alkyl, hydroxy, trifluoromethyl,(C₁-C₆)alkoxy, —S(O)_(t)(C₁-C₆)alkyl wherein t is 0, 1 or 2, —CO₂R¹⁰ or—CONR¹¹R¹²; R² is —(CH₂)_(t)B, wherein t is 0, 1, 2 or 3, and B ishydrogen, phenyl, napthyl or a 5 or 6 membered heteroaryl groupcontaining from one to four heteroatoms in the ring, and wherein each ofthe foregoing phenyl, naphthyl and heteroaryl groups may optionally besubstituted with one or more substituents independently selected fromchloro, fluoro, bromo, iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkoxy-(C₁-C₆)alkyl-, trifluoromethyl, trifluoromethoxy, cyano,hydroxy, —COOH and —SO_(n)(C₁-C₆)alkyl wherein n is 0, 1 or 2; R³ and R⁴are each independently hydrogen, (C₁-C₄)alkyl or —(CH₂)_(q)—J wherein qis 0, 1, 2 or 3, and J is phenyl or naphthyl, wherein said phenyl ornaphthyl may be optionally substituted with one to three substituentsindependently selected from the group consisting of chloro, fluoro,bromo, iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyano and—S(O)_(k)(C₁-C₆)alkyl wherein k is 0, 1 or 2; R⁵ is hydrogen or(C₁-C₃)alkyl; R⁶ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally substituted with (C₁-C₆)alkoxy or one to threefluorine atoms, or [(C₁-C₄)alkyl]aryl wherein the aryl moiety is phenyl,naphthyl, or heteroaryl-(CH₂l)_(q)—, wherein the heteroaryl moiety isselected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl,benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one,two, three or four, and wherein said aryl and heteroaryl moieties mayoptionally be substituted with one or more substituents independentlyselected from the group consisting of chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyano and—SO_(g)(C₁-C₆)alkyl, wherein g is zero, one or two; R⁷ is selected fromthe group consisting of hydrogen, (C₁-C₆)alkyl, [(C₁-C₄)alkyl]arylwherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH₂)_(r)—,wherein the heteroaryl moiety is selected from the group consisting ofpyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl andbenzisothiazolyl and r is zero, one, two, three or four, and whereinsaid aryl and heteroaryl moieties may optionally be substituted with oneor more substituents independently selected from the group consisting ofchloro, fluoro, bromo, iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,trifluoromethyl, —C(═O)-(C₁-C₆)alkyl, cyano and —SO_(j)(C₁-C₆)alkyl,wherein j is zero, one or two; or R⁶ and R⁷ taken together form a 2 to 4carbon chain; R⁸ is hydrogen or (C₁-C₃)alkyl; R⁹ is hydrogen or(C₁-C₆)alkyl; or R⁶ and R⁹, together with the nitrogen atom to whichthey are attached, form a 5 to 7 membered heteroalkyl ring that maycontain from zero to four heteroatoms selected from nitrogen, sulfur andoxygen; each of R¹⁰, R¹¹ and R¹² is selected, independently, from theradicals set forth in the definition of R³; or R¹¹ and R¹², togetherwith the nitrogen to which they are attached, form a 5 to 7 memberedheteroalkyl ring that may contain from zero to four heteroatoms selectedfrom nitrogen, sulfur and oxygen; and each R¹³ is, independently,(C₁-C₄)alkyl or a (C₁-C₄)methylene bridge from one of the ring carbonsof the piperazine or piperidine ring of G¹ or G², respectively, to thesame or another ring carbon or a ring nitrogen of the piperazine orpiperidine ring of G¹ or G², respectively, having an available bondingsite, or to a ring carbon of R⁶ having an available bonding site; withthe proviso that when B is hydrogen, t is not zero; and with the provisothat when the broken line in formula G² is a double bond, R⁸ is absent,and c) a 5-HT re-uptake inhibitor or a pharmaceutically acceptable saltthereof; wherein the amount of the active compounds are such that thecombination is effective in treating or preventing such disorder orcondition.
 2. A method of treating or preventing a disorder or conditionthat can be treated or prevented by enhancing serotonergicneurotransmission in a mammal in need thereof comprising administeringto said mammal therapeutically effective amounts of the active compoundsof the pharmaceutical composition according to claim
 1. 3. Apharmaceutical composition according to claim 1, wherein the 5-HTre-uptake inhibitor is sertraline or a pharmaceutically acceptable saltthereof.
 4. A method according to claim 2 wherein the disorder orcondition is selected from hypertension, depression, generalized anxietydisorder, phobias, posttraumatic stress syndrome, avoidant personalitydisorder, sexual dysfunction, eating disorders, obesity, chemicaldependencies, cluster headache, migraine, pain, Alzheimer's disease,obsessive-compulsive disorder, panic disorder, memory disorders,Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia,gastrointestinal tract disorders, negative symptoms of schizophrenia,premenstrual syndrome, Fibromyalgia Syndrome, stress incontinence,Tourette syndrome, trichotillomania, kleptomania, male impotence,cancer, chronic paroxysmal hemicrania and headache.
 5. A methodaccording to claims 2 or 4, wherein the 5-HT re-uptake inhibitor issertraline or a pharmaceutically acceptable salt thereof.